Identifying Novel leads for Chagas Disease by exploring potent analogs of lapatinib against protozoan parasites

Abstract

Neglected tropical diseases (NTDs) are endemic disease affecting over 1 billion people globally with different economies and geographies of 149 countries. As the name suggests, these NTDs are rife among the impoverished populations and this lacks the efforts to combat these diseases by private sectors. Hence there is a dire need to identify safe and effective drugs without the adverse effects of the existing drugs to improve the conditions of the people affected from NTDs. Among several NTDs caused by protozoan parasite, Chagas disease (American trypanosomiasis) is caused by the protozoan parasite Trypanosoma cruzi with estimated prevalence of 15 million. æCurrently, there are only two FDA approved drugs available in the market that came out over the past 40 years, with no other new drugs in the pipeline for the next 5 years. æAlthough analysis of protozoan kinomes shows the absence of tyrosine kinases, phosphorylation of tyrosine occurs, presumably via dual-specificity protein kinases. We therefore hypothesized that human tyrosine kinase inhibitors should inhibit those parasite kinases that phosphorylate tyrosine and also could impact parasite growth. Noting that analogs of the approved human EGFR inhibitor lapatinib show anti-Trypanosoma brucei activity, we tested these against T cruzi and have observed a range of potencies. In this poster we report a potent T. cruzi growth inhibitor analog designed and synthesized in our lab NEU-924 (80 nM). We will report the structure-activity relationships obtained from these efforts, and our future plans for lead optimization for anti Chagas treatments